All mammalian cells require energy to live and grow. Cells obtain this energy by metabolizing food molecules. The vast majority of normal cells utilize a single metabolic pathway to metabolize their food. The first step in this metabolic pathway is the partial degradation of glucose molecules to pyruvate in a process known as glycolysis or glycolytic cycle. The pyruvate is further degraded in the mitochondrion by a process known as the tricarboxylic acid (TCA) cycle to water and carbon dioxide, which is then eliminated. The critical link between these two processes is a large multi-subunit enzyme complex known as the pyruvate dehydrogenase ("PDH") complex (hereinafter "PDC"). PDC functions as a catalyst which funnels the pyruvate from the glycolytic cycle to the TCA cycle.
Most cancers display profound perturbation of energy metabolism. This change in energy metabolism represents one of the most robust and well-documented correlates of malignant transformation.
Because tumor cells degrade glucose largely glycolytically, i.e., without the TCA cycle, large amounts of pyruvate must be disposed of in several alternate ways. One major pathway used for disposal of excess pyruvate involves the joining of two pyruvate molecules to form the neutral compound acetoin. This generation of acetoin is catalyzed by a tumor-specific form of PDC. Although the TCA cycle still functions in cancer cells, the tumor cell TCA cycle is a variant cycle which depends on glutamine as the primary energy source. Tumor-specific PDC plays a regulatory role in this variant TCA cycle. Thus, inhibition or inactivation of a single enzyme, namely tumor-specific PDC can block large scale generation of ATP and reducing potential in tumor cells.
In spite of the extensive work characterizing tumor cell metabolism, the systematic alteration of tumor cell energy metabolism has remained unexploited as a target for cancer chemotherapy. Many malignant diseases continue to present major challenges to clinical oncology. For example prostrate cancer is the second most common cause of cancer death in men. Current treatment protocols rely primarily on hormonal manipulations. However, in spite of initial high response rates, patients often develop hormone-refractory tumors, leading to rapid disease progression with poor prognosis. Overall, the results of cytotoxic chemotherapy have been disappointing, indicating a long felt need for new approaches to prevention and treatment of advanced cancers. Other diseases resulting from abnormal cell replication, for example metastatic melanomas, brain tumors of glial origin (e.g. astrocytomas), and lung adenocarcinoma, are also highly aggressive malignancies with poor prognosis. The incidence of melanoma and lung adenocarcinoma has been increasing significantly in recent years. Surgical treatments of brain tumors often fail to remove all tumor tissues, resulting in recurrences. Systemic chemotherapy is hindered by blood barriers. Therefore, there is an urgent need for new approaches to the treatment of human malignancies including advanced prostate cancer, melanoma, brain tumors, and other malignancies such as neuroblastomas, lymphomas and gliomas.
The development of the methods and compositions of the present invention was guided by the theory that metabolic traits distinguishing tumors from normal cells can lead to targets for therapeutic intervention. For instance, tumor cells appear to function metabolically through a tumor-specific PDC. Thus, inhibitors of this enzyme complex can be used to block tumor cell metabolism, thereby resulting in selective tumor cell death.
Anti-cancer activity has been proposed for certain palladium containing lipoate compounds, wherein the specific agent causing the anti-cancer effect was identified as the palladium. U.S. Pat. Nos. 5,463,093 and 5,679,679. Unlike the prior art, the present invention relates to a new class of lipoate compounds which do not contain palladium, yet surprisingly possess potent anti-cancer activity. These compounds are believed to function through PDC, and thereby provide an effective counter-measure against cancer and other pathological or pathogenic cells that show correspondingly altered energy metabolism.
Thus, it is a general object of the invention to provide a new class of therapeutic agents that effectively target and kill tumor cells.
It is another object of the invention to provide pharmaceutical compositions comprising lipoic acid derivatives and a pharmaceutically acceptable carrier capable of specifically targeting and killing tumor cells.
It is also an object of this invention to provide a method of prophylactic or therapeutic treatment for a variety of cancers using the lipoic acid derivatives described herein.
It is another object of this invention to provide prophylactic or therapeutic treatment of pathologies such as bacterial, fungal, plant and protozoan infections of humans and other animals using the lipoic acid derivatives described herein.